UCK2 promotes intrahepatic cholangiocarcinoma progression and desensitizes cisplatin treatment by PI3K/AKT/mTOR/autophagic axis

Abstract

AbstractIntrahepatic cholangiocarcinoma (iCCA) is a highly aggressive tumor with extremely poor prognosis due to the low resection rate, high recurrence rate and drug resistance. Uridine-cytidine kinase 2 (UCK2) is proved to promote progression and drug resistance of various carcinomas by regulating pyrimidine metabolism. However, the role of UCK2 in progression and drug resistance of iCCA was largely unclear. Gene expression matrices were obtained from public database and were verified by qRT-PCR using tumor sample from Sun Yat-sen University Cancer Center. Knockdown and overexpression of UCK2 were used to evaluate the effects of UCK2 on carcinogenesis and cisplatin response in iCCA. CCK8-kit assays and plate clone formation assays were performed to detect the effect of UCK2 on proliferative activity of tumor cells. Western blotting was performed to investigate protein level of UCK2 and the relevant biomarkers of PI3K/AKT/mTOR/autophagic axis. Cell migration and invasion were assessed by using wound-healing and transwell assays. UCK2 expression was detected elevated in iCCA tissues compared with adjacent normal tissues. Biologically, overexpression of UCK2 can promote proliferation of iCCA cells, and desensitizes iCCA to cisplatin in both in vivo and in vitro models. Mechanistically, UCK2 promote iCCA progression and cisplatin resistance through inhibition of autophagy by activating the PI3K/AKT/mTOR signaling pathway. Clinically, higher UCK2 expression in iCCA tumor was associated with aggressive tumor features, poorer survival and lower sensitivity of chemotherapy. UCK2 promotes iCCA progression and desensitizes cisplatin treatment by regulating PI3K/AKT/mTOR/autophagic axis. UCK2 exhibited potential as a biomarker in predicting prognosis and drug sensitivity of iCCA patients.